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© 2015 Hoffmann et al.An efficient approach to characterizing the disease burden of rare genetic variants is to impute them into large well-phenotyped cohorts with existing genome-wide genotype data using large sequenced referenced panels. The success of t

BackgroundAlthough most epidemiological studies suggest that non-steroidal anti-inflammatory drug use is inversely associated with prostate cancer risk, the magnitude and specificity of this association remain unclear.MethodsWe examined self-reported aspirin and ibuprofen use in relation to prostate cancer risk among 29 450 men ages 55-74 who were initially screened for prostate cancer from 1993 to 2001 in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Men were followed from their first screening exam until 31 December 2009, during which 3575 cases of prostate cancer were identified.ResultsAfter adjusting for potential confounders, the hazard ratios (HRs) of prostate cancer associated with

Research on the relation between phytoestrogens and breast cancer risk has been limited in scope. Most epidemiologic studies have involved Asian women and have examined the effects of traditional soy foods (e.g., tofu), soy protein, or urinary excretion of phytoestrogens. The present study extends this research by examining the effects of a spectrum of phytoestrogenic compounds on breast cancer risk in non-Asian US women. African-American, Latina, and White women aged 35-79 years, who were diagnosed with breast cancer between 1995 and 1998, were compared with women selected from the general population via random digit dialing. Interviews were conducted with 1,326 cases and 1,657 controls. Usual intake of specific phytoestrogenic compounds was assessed via a food frequency questionnaire and a newly developed nutrient database. Phytoestrogen intake was not associated with breast cancer risk (odds ratio = 1.0, 95% confidence interval: 0.80, 1.3 for the highest vs. lowest quartile). Results were similar for pre- and postmenopausal women, for women in each ethnic group, and for all seven phytoestrogenic compounds studied. Phytoestrogens appear to have little effect on breast cancer risk at the levels commonly consumed by non-Asian US women: an average intake equivalent to less than one serving of tofu per week.

Research on the relation between phytoestrogens and breast cancer risk has been limited in scope. Most epidemiologic studies have involved Asian women and have examined the effects of traditional soy foods (e.g., tofu), soy protein, or urinary excretion of phytoestrogens. The present study extends this research by examining the effects of a spectrum of phytoestrogenic compounds on breast cancer risk in non-Asian US women. African-American, Latina, and White women aged 35-79 years, who were diagnosed with breast cancer between 1995 and 1998, were compared with women selected from the general population via random digit dialing. Interviews were conducted with 1,326 cases and 1,657 controls. Usual intake of specific phytoestrogenic compounds was assessed via a food frequency questionnaire and a newly developed nutrient database. Phytoestrogen intake was not associated with breast cancer risk (odds ratio = 1.0, 95% confidence interval: 0.80, 1.3 for the highest vs. lowest quartile). Results were similar for pre- and postmenopausal women, for women in each ethnic group, and for all seven phytoestrogenic compounds studied. Phytoestrogens appear to have little effect on breast cancer risk at the levels commonly consumed by non-Asian US women: an average intake equivalent to less than one serving of tofu per week.

The etiology of testicular germ cell tumors (TGCTs) is poorly understood, with cryptorchidism and family history being the only well-established risk factors. Body size, age at puberty, and dairy consumption, however, have been suggested to be related to TGCTs. To clarify the relation of these variables to TGCT risk and to one another, the authors analyzed data from 767 cases and 928 controls enrolled in the Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study (2002-2005). Overall, increased height was significantly related to risk (odds ratio (OR) = 1.83, 95% confidence interval (CI): 1.36, 2.45), though body mass index was not (OR = 1.06, 95% CI: 0.66, 1.69). There was no association with age at puberty, based on ages at first shaving (OR = 1.29, 95% CI: 0.96, 1.73), voice changing (OR = 0.97, 95% CI: 0.71, 1.32), and nocturnal emissions (OR = 1.00, 95% CI: 0.73, 1.37). Similarly, there was no relation with dairy consumption at any age between birth and 12th grade. These results suggest that height is a risk factor for TGCTs, but the relation is unlikely explained by childhood dairy consumption. As adult height is largely determined in the first 2 years of life, increased attention to events in this interval may help elucidate the etiology of TGCTs. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure., Methods: Using resources from colorectal cancer consortia including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score including 141 variants associated with CRC risk., Results: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking [RERI = 0.24, 95% confidence interval, CI, (0.13, 0.36)], ever smoking [0.11 (0.05, 0.16)], high BMI [female 0.09 (0.05, 0.13), male 0.10 (0.05, 0.14)], or high red meat intake [highest versus lowest quartile 0.18 (0.09, 0.27)] was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/NSAID use [-0.16 (-0.20, -0.11)] or higher intake of fruit, fiber, or calcium [highest quartile versus lowest quartile -0.12 (-0.18, -0.050); -0.16 (-0.23, -0.09); -0.11 (-0.18, -0.05), respectively] than those with average genetic susceptibility., Conclusions: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention., Competing Interests: Conflict of Interest: SB Gruber: Brogent International LLC, co-founder, not related to submitted work. All other authors do not have any conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Lung cancer in women is a modern epidemic and represents a global health crisis. Cigarette smoking remains the most important risk factor for lung cancer in all patients and, among women globally, rates of smoking continue to increase. Although some data exist supporting sex-based differences across the continuum of lung cancer, there is currently a dearth of research exploring the differences in risk, biology, and treatment outcomes in women. Consequently, the American Cancer Society National Lung Cancer Roundtable recognizes the urgent need to promote awareness and future research that will close the knowledge gaps regarding lung cancer in women. To this end, the American Cancer Society National Lung Cancer Roundtable Task Group on Lung Cancer in Women convened a summit undertaking the following to: (1) summarize existing evidence and identify knowledge gaps surrounding the epidemiology, risk factors, biologic differences, and outcomes of lung cancer in women; (2) develop and prioritize research topics and questions that address research gaps and advance knowledge to improve quality of care of lung cancer in women; and (3) propose strategies for future research. PLAIN LANGUAGE SUMMARY: Lung cancer is the leading cause of cancer mortality in women, and, despite comparatively lower exposures to occupational and environmental carcinogens compared with men, disproportionately higher lung cancer rates in women who ever smoked and women who never smoked call for increased awareness and research that will close the knowledge gaps regarding lung cancer in women., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Introduction: Among older adults without cancer, living alone is associated with poor health outcomes. However, among older adults with non-small cell lung cancer (NSCLC) who live alone, data on function, cognition, and quality of life (QOL) during systemic treatment remain limited., Materials and Methods: We enrolled adults aged ≥65 with advanced NSCLC starting a new chemotherapy, immunotherapy, and/or targeted therapy regimen with non-curative intent. Patients completed geriatric assessments including instrumental activities of daily living (IADL), Montreal Cognitive Assessment, and QOL pretreatment and at 1, 2, 4, and 6 months, or until treatment discontinuation, whichever occurred earlier. We categorized change in IADL, cognition, and QOL as stable/improved, declined with recovery, or declined without recovery using clinically meaningful definitions of change. We used multinomial logistic regression to compare change between patients who lived alone versus with others., Results: Among 149 patients, median age was 73; 21% lived alone. Pretreatment IADL, cognition, and QOL scores were similar between older adults who lived alone versus with others. During NSCLC treatment, older adults who lived alone had similar trajectories of function (52% functional decline vs 38%), cognition (43% cognitive decline vs 50%), and QOL (45% QOL decline vs 44%) compared with those who lived with others. In unadjusted analyses, patients who lived alone were more likely to develop functional decline with recovery (reference category: stable/improved function) than those who lived with others (relative risk ratio 4.07, 95% CI 1.14-14.6, p = 0.03). However, this association was not observed after adjusting for age, race, prior NSCLC treatment, current treatment group, and pretreatment geriatric assessment differences. There were no differences in cognitive or QOL trajectories in unadjusted or adjusted analyses., Discussion: Approximately half of older adults with advanced NSCLC who lived alone were able to maintain their function, cognition, and QOL during NSCLC treatment, which was similar to older adults who lived with others. Many older adults with advanced NSCLC who live alone can receive systemic treatment with individualized supportive care., Competing Interests: Declaration of Competing Interest SS reported conflicts of interest outside the submitted work (consultant/advisory to Oncohost). AIV reported conflicts of interest outside the submitted work (consultant/advisory to Merus and AstraZeneca). LCS has received research funding from AstraZeneca awarded directly to her institution. MLW reported conflicts of interest outside of the submitted work (royalties from UpToDate; immediate family member is an employee of Genentech with stock ownership). The remaining authors have no conflicts to report., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Observational research is important for understanding the real-world benefits of advancements in lung cancer care. Integrated health care systems, such as Kaiser Permanente Northern California, have extensive electronic health records suitable for such research, but the generalizability of their populations is often questioned., Methods: Leveraging data from the California Cancer Registry, the authors compared distributions of demographic and clinical characteristics, in addition to neighborhood and environmental conditions, between patients diagnosed with lung cancer from 2015 through 2019 at Kaiser Permanente Northern California, National Cancer Institute-designated cancer centers (NCICCs), and all other non-NCICC hospitals within the same catchment area., Results: Of 20,178 included patients, 30% were from Kaiser Permanente Northern California, 8% from NCICCs, and 62% from other non-NCICC hospitals. Compared to NCICC patients, Kaiser Permanente Northern California patients were more similar to other non-NCICC patients on most characteristics. Compared to other non-NCICC patients, Kaiser Permanente Northern California patients were slightly older, more likely to be female, and less likely to be Hispanic or Asian/Pacific Islander and to reside in lower socioeconomic status (SES) neighborhoods. In contrast, NCICC patients were younger, less likely to be female or from non-Asian/Pacific Islander minoritized racial groups, and more likely to present with early-stage disease and adenocarcinoma and to reside in neighborhoods with higher SES and lower air pollution than Kaiser Permanente Northern California or other non-NCICC patients., Discussion: Patients from Kaiser Permanente Northern California, compared to NCICCs, are more broadly representative of the underlying patient population with lung cancer., Conclusion: Research using electronic health record data from integrated health care systems can contribute generalizable real-world evidence to benchmark and improve lung cancer care., Competing Interests: Conflicts of Interest Drs Liu, Velotta, and Sakoda have received research funding from AstraZeneca that was awarded to their institution. Dr Wong reports conflicts of interest outside of this work (royalties from UpToDate; immediate family member is employed by Genentech with stock ownership). An earlier version of an abstract of this work was published for the 2023 American Society for Clinical Oncology (ASCO) Annual Meeting. Copyright for materials presented remains with the authors.

Purpose: Minoritized racial/ethnic groups are historically under-represented in cancer clinical trials, which may be exacerbated in recent trials on immune checkpoint inhibitors (ICIs). We examined the representation and reporting of the racial/ethnic composition of participants in clinical trials on ICIs., Methods: We examined English full-text trials on ICIs published from 2007 to 2022. Information on trial characteristics and racial/ethnic composition of participants was extracted from published papers or ClinicalTrials.gov. Differences in participation by publication year, ICI agent, and cancer site were analyzed. Enrollment-incidence ratio (EIR) was calculated to compare the proportion of minoritized racial/ethnic group patients in US-based trials against age-adjusted cancer incidence data available for the US population. An EIR > 1 signified over-representation, whereas an EIR <1 signified under-representation., Results: Of the 471 trials examined, racial composition was unreported in 146 (31%), whereas Hispanic/Latinx ethnicity was unreported in 278 (59%). Only 30 (6%) trials reported race/ethnicity-specific results. In US-only trials (n = 174), White patients were over-represented (EIR, 1.20 [95% CI, 1.17 to 1.22]), whereas Hispanic/Latinx patients were the most under-represented (EIR, 0.35 [95% CI, 0.24 to 0.48]), followed by Black/African American patients (EIR, 0.66 [95% CI, 0.54 to 0.79]). Subgroup analyses consistently indicated over-representation of White patients across publication years (EIR, 1.19-1.24), ICI classes (EIR, 1.16-1.23), and cancer sites (EIR, 1.11-1.31), whereas Hispanic/Latinx patients were consistently under-represented. An upward trend of trial representation and reporting was observed for all minoritized racial/ethnic groups over time (trend P values ≤.05)., Conclusion: Disparities in the representation and reporting of minoritized racial/ethnic groups persist in recent trials on ICIs, necessitating collaborative efforts for improved diversity and equitable cancer treatment access.

Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk., Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated., Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10 -8 ). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10 -14 ); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10 -3 ), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk., Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use., (© 2024. The Author(s).)

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development., (© 2024. The Author(s).)

Background: Sedentary behaviours have been associated with increased risks of some common cancers in epidemiological studies; however, it is unclear if these associations are causal., Methods: We used univariable and multivariable two-sample Mendelian randomisation (MR) to examine potential causal relationships between sedentary behaviours and risks of breast, colorectal and prostate cancer. Genetic variants associated with self-reported leisure television watching and computer use were identified from a recent genome-wide association study (GWAS). Data related to cancer risk were obtained from cancer GWAS consortia. A series of sensitivity analyses were applied to examine the robustness of the results to the presence of confounding., Results: A 1-standard deviation (SD: 1.5 h/day) increment in hours of television watching increased risk of breast cancer (OR per 1-SD: 1.15, 95% confidence interval [CI]: 1.05-1.26) and colorectal cancer (OR per 1-SD: 1.32, 95% CI: 1.16-1.49) while there was little evidence of an association for prostate cancer risk (OR per 1-SD: 0.94, 95% CI: 0.84-1.06). After adjusting for years of education, the effect estimates for television watching were attenuated (breast cancer, OR per 1-SD: 1.08, 95% CI: 0.92-1.27; colorectal cancer, OR per 1-SD: 1.08, 95% CI: 0.90-1.31). Post hoc analyses showed that years of education might have a possible confounding and mediating role in the association between television watching with breast and colorectal cancer. Consistent results were observed for each cancer site according to sex (colorectal cancer), anatomical subsites and cancer subtypes. There was little evidence of associations between genetically predicted computer use and cancer risk., Conclusions: Our univariable analysis identified some positive associations between hours of television watching and risks of breast and colorectal cancer. However, further adjustment for additional lifestyle factors especially years of education attenuated these results. Future studies using objective measures of exposure can provide new insights into the possible role of sedentary behaviour in cancer development., (© 2023 World Health Organization; licensed by John Wiley & Sons Ltd. Cancer Medicine published by John Wiley & Sons Ltd.)

Background & Aims: Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death., Methods: Risk predictions for CRC and competing causes of death from a large community-based cohort were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40-60 years), end age (70-85 years), and screening interval (5-15 years). The outcomes included personalized screening ages and intervals and cost-effectiveness compared with uniform colonoscopy screening (ages 45-75, every 10 years). Key assumptions were varied in sensitivity analyses., Results: Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every 5 years from ages 40 to 85 for high-risk individuals. Nevertheless, on a population level, risk-stratified screening would increase net quality-adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening or reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test., Conclusions: Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The updated US Preventive Services Task Force guidelines on lung cancer screening have significantly expanded the population of screening eligible adults, among whom the balance of benefits and harms associated with lung cancer screening vary considerably. Clinical adjuncts are additional information and tools that can guide decision-making to optimally screen individuals who are most likely to benefit. Proposed adjuncts include integration of clinical history, risk prediction models, shared-decision-making tools, and biomarker tests at key steps in the screening process. Although evidence regarding their clinical utility and implementation is still evolving, they carry significant promise in optimizing screening effectiveness and efficiency for lung cancer., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC., Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk., Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO)., Results: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10 -8 ) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10 -8 ). No interactions were observed for dietary and total folate., Conclusions: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice., (© 2023. Springer Nature Limited.)

Background: At least 10% of lung cancers arise in adults who have never used tobacco. Data remain inconclusive on whether lung cancer incidence has been increasing among adults who have never used tobacco., Research Question: How have age-adjusted incidence rates of lung cancer changed temporally, especially among adults who have never used tobacco?, Study Design and Methods: Trends in lung cancer incidence were examined using linked electronic health record and cancer registry data on a dynamic cohort of adults ≥ 30 years of age at risk of incident lung cancer between January 1, 2007, and December 31, 2018, from an integrated health-care system in northern California. Truncated age-adjusted lung cancer incidence rates and average annual percentage change (AAPC) in rates were estimated, overall and separately for adults who have ever and never used tobacco by age, sex, and race or ethnicity., Results: The cohort included 3,751,348 adults (52.5% female, 48.0% non-Hispanic White, 63.1% have never used tobacco), among whom 18,627 (52.7% female, 68.6% non-Hispanic White, 15.4% have never used tobacco) received a diagnosis of lung cancer. The overall lung cancer incidence rate declined from 91.1 to 63.7 per 100,000 person-years between 2007 and 2009 and between 2016 and 2018 (AAPC, -3.9%; 95% CI, -4.2% to -3.6%). Among adults who have ever used tobacco, incidence rates declined overall from 167.0 to 113.4 per 100,000 person-years (AAPC, -4.2%; 95% CI, -4.4% to -3.9%) and, to varying degrees, within all age, sex, and racial or ethnic groups. Among adults who have never used tobacco, incidence rates were relatively constant, with 3-year-period estimates ranging from 19.9 to 22.6 per 100,000 person-years (AAPC, 0.9%; 95% CI, -0.3% to 2.1%). Incidence rates for adults who have never used tobacco seemed stable over time, within age, sex, and racial or ethnic groups, except for those of Asian and Pacific Islander (API) origin (AAPC, 2.0%; 95% CI, 0.1%-3.9%), whose rates were about twice as high compared with their counterparts., Interpretation: These observed trends underscore the need to elucidate further the cause of lung cancer in adults who have never used tobacco, including why incidence is higher and rising in API adults who have never used tobacco., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer., Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies., (©2023 The Authors; Published by the American Association for Cancer Research.)

Our recently published study of >2.4 million adults in Northern California indicated that current versus never-tobacco smoking was associated with lower risk of SARS-CoV-2 infection and less severe coronavirus disease 2019 (COVID-19). We extended this research by evaluating whether these associations were moderated by socio-demographic factors and medical comorbidities. This retrospective cohort study of 1,885,826 adults with current or never-smoking status in Kaiser Permanente Northern California from 3/5/2020 (baseline) to 12/31/2020 (pre-vaccine) included electronic health record-based socio-demographics (sex, age, race/ethnicity, neighborhood deprivation index (NDI)) and medical comorbidities (obesity, cardiovascular conditions, diabetes, renal disease, respiratory conditions). We estimated the adjusted risk of SARS-CoV-2 infection and hospitalization (≤30 days of infection) associated with smoking status using Cox proportional hazard regression models. We estimated associations within subgroups of socio-demographics and comorbidities, and tested for effect modification using interaction terms. During the study, 35,627 patients had SARS-CoV-2 infection. Current versus never-smoking status was associated with lower adjusted rates of SARS-CoV-2 infection (aHR ranging from 0.51 to 0.89) and hospitalization (aHR ranging from 0.32 to 0.70) within nearly every socio-demographic and comorbidity subgroup. Statistically significant interactions showed that the magnitude of protection for SARS-CoV-2 infection varied by sex, age, race/ethnicity, NDI, cardiovascular conditions and diabetes, and for SARS-CoV-2 hospitalization by age and renal disease. Taken together, results indicated that while some socio-demographics and comorbidities moderated the associations, the lower risk of SARS-CoV-2 infection and hospitalization associated with current versus never-smoking status persisted among patients regardless of socio-demographics or comorbidities., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Judith J. Prochaska, PhD, MPH, has provided consultation to pharmaceutical and technology companies that make medications and other treatments for quitting smoking and has served as an expert witness in lawsuits against the tobacco companies. All other authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Optimal time to surgery for lung cancer is not well established. We aimed to assess whether time to surgery correlates with outcomes., Methods: We assessed patients 18-84 years old who were diagnosed with stage I/II lung cancer at our integrated healthcare system from 2009 to 2019. Time to surgery was defined to start with disease confirmation (imaging or biopsy) prior to the surgery scheduling date. Outcomes of unplanned return to care within 30 days of lung cancer surgery, all-cause mortality, and disease recurrence were compared based on time to surgery before and after 2, 4, and 12 weeks., Results: Of 2861 included patients, 70% were over 65 years old and 61% were female. Time to surgery occurred in 1-2 weeks for 6%, 3-4 weeks for 31%, 5-12 weeks for 58%, and 13-26 weeks for 5% of patients. Patients with time to surgery > 4 (vs. ≤ 4) weeks had greater risk of both death (hazard ratio (HR) 1.18, 95% confidence interval (CI) 1.00-1.39) and recurrence (HR 1.33, 95% CI 1.10-1.62). Associations were not statistically significant when dichotomizing time to surgery at 2 or 12 weeks for death (2 week HR 1.23, 95% CI 0.93-1.64; 12 week HR 1.35, 95% CI 0.97-1.88) and recurrence (2 week HR 1.54, 95% CI 0.85-2.80; 12 week HR 2.28, 95% CI 0.80-6.46)., Conclusions: Early stage lung cancer patients with time to surgery within 4 weeks experienced lower rates of recurrence. Optimal time to surgical resection may be shorter than previously reported., (© 2023. The Author(s).)

Introduction: Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management., Methods: Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases., Results: The proportions of MSI-high, CIMP-high, and BRAF -mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF -mutated) (all Ptrend <0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors ( P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend <0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend., Discussion: Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups., (Copyright © 2023 by The American College of Gastroenterology.)

Background: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer., Methods: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia., Results: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33)., Conclusions: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response., Impact: These findings can guide potential prevention treatments., (©2022 American Association for Cancer Research.)

Background: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance., Methods: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group)., Results: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity., Conclusions: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort., Impact: The proposed model has potential utility in risk-stratified colorectal cancer prevention., (©2023 American Association for Cancer Research.)

Background: The pathogenic effect of colorectal tumor molecular features may be influenced by several factors, including those related to microbiota, inflammation, metabolism, and epigenetics, which may change along colorectal segments. We hypothesized that the prognostic association of colon cancer location might differ by tumor molecular characteristics., Methods: Utilizing a consortium dataset of 13,101 colorectal cancer cases, including 2994 early-onset cases, we conducted survival analyses of detailed tumor location stratified by statuses of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF oncogenic mutation., Results: There was a statistically significant trend for better colon cancer-specific survival in relation to tumor location from the cecum to sigmoid colon (P trend  = 0.002), excluding the rectum. The prognostic association of colon location differed by MSI status (P interaction  = 0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better colon cancer-specific survival [P trend  < 0.001; multivariable hazard ratio (HR) for the sigmoid colon (vs. cecum), 0.80; 95% confidence interval (CI) 0.70-0.92], whereas MSI-high tumors demonstrated a suggestive cecum-to-sigmoid trend for worse survival (P trend  = 0.020; the corresponding HR, 2.13; 95% CI 1.15-3.92). The prognostic association of colon tumor location also differed by CIMP status (P interaction  = 0.003) but not significantly by age, stage, or other features. Furthermore, MSI-high status was a favorable prognostic indicator in all stages., Conclusions: Both detailed colonic location and tumor molecular features need to be accounted for colon cancer prognostication to advance precision medicine. Our study indicates the important role of large-scale studies to robustly examine detailed colonic subsites in molecular oncology research., (© 2023. Japanese Society of Gastroenterology.)

Background: Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease., Methods: We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables., Results: Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control)., Conclusions: In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome., (© The Author(s) 2022. Published by Oxford University Press.)

Human bulk tissue samples comprise multiple cell types with diverse roles in disease etiology. Conventional transcriptome-wide association study approaches predict genetically regulated gene expression at the tissue level, without considering cell-type heterogeneity, and test associations of predicted tissue-level expression with disease. Here we develop MiXcan, a cell-type-aware transcriptome-wide association study approach that predicts cell-type-level expression, identifies disease-associated genes via combination of cell-type-level association signals for multiple cell types, and provides insight into the disease-critical cell type. As a proof of concept, we conducted cell-type-aware analyses of breast cancer in 58,648 women and identified 12 transcriptome-wide significant genes using MiXcan compared with only eight genes using conventional approaches. Importantly, MiXcan identified genes with distinct associations in mammary epithelial versus stromal cells, including three new breast cancer susceptibility genes. These findings demonstrate that cell-type-aware transcriptome-wide analyses can reveal new insights into the genetic and cellular etiology of breast cancer and other diseases., (© 2023. The Author(s).)

Introduction: The relationship between tobacco smoking status and SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) severity is highly debated. We conducted a retrospective cohort study of >2.4 million adults in a large healthcare system to evaluate whether smoking is associated with SARS-CoV-2 infection and disease severity., Aims and Methods: This retrospective cohort study of 2,427,293 adults in KPNC from March 5, 2020 (baseline) to December 31, 2020 (pre-vaccine) included smoking status (current, former, never), socio-demographics, and comorbidities from the electronic health record. SARS-CoV-2 infection (identified by a positive PCR test) and COVID-19 severity (hospitalization, ICU admission or death ≤ 30 days of COVID-19 diagnosis) were estimated in time-to-event analyses using Cox proportional hazard regression models adjusting for covariates. Secondary analyses examined COVID-19 severity among patients with COVID-19 using logistic regression., Results: During the study, 44,270 patients had SARS-CoV-2 infection. Current smoking was associated with lower adjusted rates of SARS-CoV-2 infection (aHR = 0.64 95% CI: 0.61-0.67), COVID-19-related hospitalization (aHR = 0.48 95% CI: 0.40-0.58), ICU admission (aHR = 0.62 95% CI: 0.42-0.87), and death (aHR = 0.52 95% CI: 0.27-0.89) than never-smoking. Former smoking was associated with a lower adjusted rate of SARS-CoV-2 infection (aHR = 0.96 95% CI: 0.94-0.99) and higher adjusted rates of hospitalization (aHR = 1.10 95% CI: 1.03-1.08) and death (aHR = 1.32 95% CI: 1.11-1.56) than never-smoking. Logistic regression analyses among patients with COVID-19 found lower odds of hospitalization for current versus never-smoking and higher odds of hospitalization and death for former versus never-smoking., Conclusions: In the largest US study to date on smoking and COVID-19, current and former smoking showed lower risk of SARS-CoV-2 infection than never-smoking, while a history of smoking was associated with higher risk of severe COVID-19., Implications: In this cohort study of 2.4 million adults, adjusting for socio-demographics and medical comorbidities, current tobacco smoking was associated with a lower risk of both SARS-CoV-2 infection and severe COVID-19 illness compared to never-smoking. A history of smoking was associated with a slightly lower risk of SARS-CoV-2 infection and a modestly higher risk of severe COVID-19 illness compared to never-smoking. The lower observed COVID-19 risk for current versus never-smoking deserves further investigation. Results support prioritizing individuals with smoking-related comorbidities for vaccine outreach and treatments as they become available., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To compare survival among patients with head and neck cancer before and after implementing a weekly multidisciplinary clinic and case conference., Methods: A retrospective cohort study with chart review was conducted of 3081 patients (1431 preimplementation, 1650 postimplementation) diagnosed with stage I-IVB tumors in the oral cavity, oropharynx, hypopharynx, nasopharynx, or larynx. Pre- and postimplementation differences in overall and disease-specific survival 1, 2, and 3 years after diagnosis were assessed with unadjusted Kaplan-Meier curves and multivariable Cox proportional hazard regression models adjusted for demographic characteristics, comorbidity burden, smoking status, tumor site and stage, p16 status for oropharyngeal squamous cell cancer, and initial treatment modality., Results: Patients less commonly presented with oropharyngeal squamous cell cancer and advanced tumors (III-IVB) and received primary treatment with surgery alone or with adjuvant therapy preimplementation than postimplementation. Overall survival at 3 years was 77.1% and 79.9% (P = .07) and disease-specific survival was 84.9% and 87.5% (P = .05) among pre- and postimplementation patients, respectively. At 3 years, preimplementation patients had slightly poorer overall (hazard ratio, 1.20; 95% CI, 1.02-1.40) and disease-specific (hazard ratio, 1.26; 95% CI, 1.03-1.54) adjusted survival than postimplementation patients. In unadjusted and adjusted analyses, survival improvements were more pronounced among patients with advanced disease., Discussion: A multidisciplinary clinic and case conference were associated with improved outcomes among patients with head and neck cancer, especially those with advanced tumors., Implications for Practice: All patients with head and neck cancer should receive multidisciplinary team management, especially those with advanced tumors., (© American Academy of Otolaryngology-Head and Neck Surgery Foundation 2021.)